Peroxisome proliferator-activated receptor-g coactivator-1 (PGC-1) is a novel transcriptional co-activator of a series of nuclear receptors including peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor involved in adipogenesis and a functional receptor for thiazolidinediones [1,2]. Similarly, PGC-1 is a coactivator of peroxisome proliferator-activated receptor-a (PPAR-a), which plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid beta-oxidation enzymes [3]. Studies in cultured muscle-cell lines show that PGC-1 stimulates mitochondrial biogenesis and respiration through an induction of uncoupling protein 2 and through regulation of the nuclear respiratory factors [2]. Thus, PGC-1 is a key factor in the stimulation of adaptive thermogenesis, e. g. during high caloric diets or cold exposure. It has recently Diabetologia (2001)

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Aims/hypothesis: The cytokine interleukin 6 (IL-6) is an essential regulator of the acute phase response associated with insulin-resistant states including type 2 diabetes and obesity. Three polymorphisms at positions −597, −572, and −174 of the IL6 promoter have been reported to influence IL6 transcription. The aim of this study was to investigate whether the IL6 promoter polymorphisms were associated with features of the WHOdefined metabolic syndrome and related quantitative traits in 7,553 Caucasian Danes. Methods: Using analysis of PCR-generated primer extension products by mass spectrometry we examined −597 G/A, −572 G/C, and −174 G/ C IL6 variants in the population-based Inter99 study cohort of middle-aged people (n=6,164) and in a group of type 2 diabetic patients (n=1,389). Results: The −174 G/C and −597 G/A polymorphisms were in strong linkage disequilibrium (R 2 =0.95). In the Inter99 cohort the −174 G-allele was associated with insulin resistance (p<0.02) and dyslipidaemia (p<0.007) whereas the C-allele of the −572 polymorphism was associated with increased serum insulin release during an OGTT (p<0.0005). Composite genotype or haplotype analyses of all 3 IL6 promoter variants showed associations with type 2 diabetes (p<0.002), obesity (p<0.02), and the metabolic syndrome (p<0.01). Conclusions:The present studies suggest that single-nucleotide polymorphisms and composite genotypes or haplotypes of the IL6 promoter may be associated with several features of the metabolic syndrome in Caucasians.

OBJECTIVE -Insulin resistance and impaired ␤-cell function are key elements in the pathogenesis of type 2 diabetes. We aimed to develop valid algorithms for estimation of the insulin sensitivity index (S I ) and acute insulin response (AIR) derived from simple and cheap physiological measurements that could be used in large-scale metabolic, genetic, and epidemiological studies.RESEARCH DESIGN AND METHODS -For our purpose, data from an oral glucose tolerance test (OGTT) (18 samples during 240 min) and a tolbutamide-modified intravenous glucose tolerance test (IVGTT) (33 samples during 180 min) from 258 individuals with fasting plasma glucose Ͻ7 mmol/l and 2-h plasma glucose Ͻ7.8 mmol/l were used for model development and internal validation. Data from an additional 28 individuals were used for external validation. Bergman's minimal model was used to calculate S I , and the trapezoidal method was used to calculate AIR 0 -8 min . Multiple linear regression was applied to derive predictive equations of log(S I ) and log(AIR 0 -8 min ) using data on sex, BMI, plasma glucose, and serum insulin levels obtained during the OGTT.RESULTS -We demonstrate that it is possible to obtain estimates of S I (BIGTT-S I ) and AIR (BIGTT-AIR) that are highly correlated to IVGTT-derived values of S I (R 2 ϭ 0.77) and AIR (R 2 ϭ 0.54). In the two validation datasets we obtained similar results.CONCLUSIONS -Data from OGTTs can provide accurate measures of insulin sensitivity and ␤-cell function, which can be used in large scale metabolic, genetic, and epidemiological studies. Diabetes Care 30:257-262, 2007

The high-affinity sulfonylurea receptor (SUR1) is, as a subunit of the ATP-sensitive potassium channel, an important regulator of insulin secretion in the pancreatic beta-cell. The aim of this study was to examine if genetic variability of the SUR1 gene was associated with NIDDM or altered pancreatic beta-cell function. Mutational analysis of all the 39 SUR1 exons, including intron-exon boundaries, in 63 NIDDM patients revealed two missense variants, five silent variants in the coding region, and four intron variants. The two missense variants (Asp673Asn and Ser1369Ala) and two sequence variants (ACC-->ACT, Thr759Thr and a c-->t intron variant in position -3 of the exon 16 splice acceptor site) were examined for association with NIDDM and for a possible influence on insulin and C-peptide secretion after intravenous glucose and tolbutamide loads in a random sample of unrelated, healthy, young Danish Caucasians. The Asp673Asn variant in exon 14 was only identified in one NIDDM patient, and the allelic frequency of the Ser1369Ala was similar among 247 control subjects (0.38 [95% CI 0.34-0.42]) and 406 NIDDM patients (0.40 [0.37-0.43]). The allelic frequency of the silent exon 18 Thr775Thr variant was 0.051 (0.035-0.067) in NIDDM patients (n=392) and 0.027 (0.013-0.041) in control subjects (n=246; chi2=4.99, P=0.03). The allelic frequency of the intron variant was similar among NIDDM patients (0.45 [0.42-0.48]) and control subjects (0.44 [0.40-0.48]). Of 386 NIDDM patients, 17 had the combined genotype exon 18 C/T and intron -3c/-3t (0.044 [0.024-0.064]), whereas 3 of 243 control subjects had the same combined genotype (0.012 [0-0.026]; chi2=4.87, P=0.03; odds ratio: 3.69 [1.07-12.71]). Of 380 unrelated, healthy, young Danish Caucasians, 10 (0.026 [0.010-0.042]) had the combined at-risk genotype. These subjects had, on average, a 50% reduction in serum C-peptide and a 40% reduction in serum insulin responses upon tolbutamide injection (P=0.002 and P=0.05, respectively) but normal serum C-peptide and insulin responses upon glucose injection. In conclusion, a silent polymorphism in exon 18 of the SUR1 gene is associated with NIDDM in a Danish Caucasian population. In combination with an intron variant, the association is higher, and young, healthy carriers of the intragenic combination have reduced serum C-peptide and insulin responses to a tolbutamide load.

OBJECTIVE: The gene that codes for a novel uncoupling protein, UCP2, has been linked to obesity in animal models. Markers encompassing the UCP2 locus have been linked to energy expenditure in humans. We studied the role of a common amino acid substitution, replacing an alanine (A) with a valine (V) at codon 55, of the coding region of the UCP2 gene for 24-h energy expenditure and respiratory quotient (RQ) in healthy subjects METHODS: 24-h energy expenditure and RQ were measured in calorimeters in 60 healthy subjects. The UCP2 polymorphism was determined by restriction fragment length polymorphism-generating polymerase chain reaction. RESULTS: Age, gender and body fat were not different between groups, the number of subjects in each groups was AaA: 35% (n 21), AaV: 48% (n 29), and VaV: 17% (n 10). Twenty-four-hour energy expenditure, adjusted for fat-free mass, fat mass, and spontaneous physical activity, was 311 kJad lower (95% con®dence interval: 24 ± 598 kJad, P 0.03) in the VaV homozygotes than in the AaA and AaV genotypes. The VaV had $ 20% higher 24-h spontaneous physical activity, particularly higher at night (P`0.005). Energy expenditure due to higher spontaneous physical activity counteracted the VaV group's lower 24-h resting energy expenditure for a given body size and composition. 24-h RQ adjusted for energy balance, age, sex and spontaneous physical activity, was higher in the VaV homozygotes than in the AA and AaV groups (P`0.05). CONCLUSIONS: Subjects with the VaV genotype of the UCP2 gene exhibit an enhanced metabolic ef®ciency and lower fat oxidation than the AaA and AaV genotypes.